PB1904: TRIAL IN PROGRESS: A PHASE III STUDY OF ASCIMINIB VS AN INVESTIGATOR-SELECTED TKI IN PATIENTS WITH NEWLY DIAGNOSED CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE (CML-CP)
Authors: T. Hughes, J. Cortes, N. Takahashi, R. Larson, G. Issa, F. Bombaci, N. Ramscar, S. Kapoor, S. Ifrah, A. Hochhaus
Journal: HemaSphere (2022)

Background: The main treatment goal for patients (pts) with CML-CP is disease control. Pts may be treated with 1 of 4 tyrosine kinase inhibitors (TKIs) approved for 1st-line (1L) use: the 1st-generation TKI imatinib and the 2nd-generation (2G) TKIs bosutinib, dasatinib, and nilotinib. However, in 1L CML-CP, >50% of pts treated with imatinib develop resistance to or intolerance of therapy, and 30% to 40% of pts treated with a 2G TKI need to change therapy by 5 years. In addition, only 30% to 55% of pts achieve a deep molecular response (DMR), an important criterion for attempting treatment-free remission. While 2G TKIs yield a higher major molecular response (MMR) than imatinib, they are associated with more adverse events (AEs), which can include arterio-occlusive events. Therefore, highly potent and safe treatment options are needed for pts with 1L CML-CP. Asciminib is a recently approved drug that inhibits the BCR::ABL1 oncoprotein through a novel mechanism of action: Specifically Targeting the ABL Myristoyl Pocket (STAMP). In the phase III ASCEMBL trial in pts with CML-CP treated with ≥2 prior TKIs, asciminib resulted in improved MMR (25.5% vs 13.2%) at week 24 and fewer treatment discontinuations due to AEs (5.8% vs 21.1%) compared with bosutinib. Here we present a phase III trial evaluating asciminib vs an investigator-selected approved TKI in adult pts with newly diagnosed CML-CP. Aims: The primary objectives of this study are to assess the efficacy of asciminib vs that of an investigator-selected TKI in the 1L and compare the efficacy of asciminib with that of the stratum of pts receiving investigator-selected imatinib in the 1L via the primary endpoint of MMR at week 48. The study will be positive if either of these objectives is met. Secondary objectives include long-term efficacy outcomes and safety. Methods: This is a multicenter, open-label, randomized, phase III study (NCT04971226) of asciminib 80 mg once daily (QD) compared with an approved, investigator-selected TKI (imatinib, bosutinib, dasatinib, or nilotinib) in the 1L (expected N=402). Pts must not have received prior TKI therapy for CML except for ≤2 weeks of imatinib therapy and must have Eastern Cooperative Oncology Group performance status of 0 or 1 and provided informed consent. Pts could have received hydroxyurea or anagrelide for urgent disease control. Pts will be randomized 1:1 to the asciminib arm or investigator-selected TKI arm using 2 strata: European Treatment and Outcome Study long-term survival risk score and the control arm TKI selected by the investigator before randomization (Figure). Pts randomized to the investigator-selected TKI arm will receive their selected TKIs at approved doses: imatinib 400 mg QD, bosutinib 400 mg QD, dasatinib 100 mg QD, or nilotinib 300 mg twice daily. Pts will remain on study for 5 years after the last pt’s 1st treatment has been administered, unless they have discontinued early due to treatment failure, disease progression, intolerance, or investigator/pt decision. Pts who discontinue early will continue to be followed up for survival and disease progression until the end of the study Results: The primary endpoint is MMR at week 48. Secondary endpoints include MMR at week 96, safety, and DMR; exploratory endpoints include biomarker assessments. Image:Summary/Conclusion: This study will assess the efficacy of asciminib in adult pts with newly diagnosed CML-CP vs that of currently approved TKIs.